Crystal and solvate of 2-amino-6-benzyloxypurine and production methods thereof

ABSTRACT

The present invention can provide a solvate, a cubic crystal and a columnar crystal of 2-amino-6-benzyloxypurine by crystallization from (1) a solvent containing at least one kind of solvent selected from the group consisting of alcohol and water, (2) alcohol or (3) a water-containing solvent.

TECHNICAL FIELD

The present invention relates to a novel crystal and a solvate of2-amino-6-benzyloxypurine and production methods thereof.

BACKGROUND ART

2-Amino-6-benzyloxypurine is useful as an intermediate for theproduction of a pharmaceutical product, and there are various reports onthe production methods thereof. However, no report relates to theproduction of 2-amino-6-benzyloxypurine as a solvate (e.g., hydrate,methanolate), and there is no report relating to the production methodof the solvate.

As regards a crystal of 2-amino-6-benzyloxypurine, for example, TheJournal of Organic Chemistry, vol. 34, 2160-2163 (1969) reports that aneedle crystal can be obtained. However, the number of reports is small,with no report on a cubic crystal or a columnar crystal obtained so faror production methods thereof.

It is therefore an object of the present invention is to provide amethod for producing 2-amino-6-benzyloxypurine as a crystal having ashape so far not obtained, namely, as a cubic crystal or a columnarcrystal. Another object of the present invention is to provide a methodfor producing a 2-amino-6-benzyloxypurine solvate (particularly hydrateor alcoholate). A further object of the present invention is to providea cubic crystal, a columnar crystal and a solvate (particularly hydrateor alcoholate) of 2-amino-6-benzyloxypurine.

DISCLOSURE OF THE INVENTION

The present inventors have intensively studied in an attempt to achievethe above-mentioned objects, and found a solvate (particularly hydrateand alcoholate), a cubic crystal and a columnar crystal of2-amino-6-benzyloxypurine heretofore not obtained and production methodsthereof, which resulted in the completion of the present invention.

That is, the present invention provides the following [1]-[12].

[1] A 2-amino-6-benzyloxypurine solvate.

[2] A 2-amino-6-benzyloxypurine hydrate.

[3] A 2-amino-6-benzyloxypurine alcoholate.

[4] A 2-amino-6-benzyloxypurine methanolate.

[5] A 2-amino-6-benzyloxypurine ethanolate.

[6] A cubic crystal of 2-amino-6-benzyloxypurine.

[7] A columnar crystal of 2-amino-6-benzyloxypurine.

[8] A production method of a cubic crystal or a columnar crystal of2-amino-6-benzyloxypurine, which comprises crystallization from asolvent containing at least one kind of solvent selected from the groupconsisting of alcohol and water.

[9] A production method of a 2-amino-6-benzyloxypurine alcoholate, whichcomprises crystallization from alcohol.

[10] A production method of a 2-amino-6-benzyloxypurine hydrate, whichcomprises crystallization from a water-containing solvent.

[11] The production method of the above-mentioned [10], wherein thewater-containing solvent is a mixed solvent of alcohol and water.

[12] The production method of the above-mentioned [10], wherein thewater-containing solvent is water.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a microscopic photograph (magnification ×100, 1graduation=0.02 mm) of a 2-amino-6-benzyloxypurine hydrate, which is acolumnar crystal obtained in Example 1.

FIG. 2 shows a differential scanning calorimetry (DSC) of a2-amino-6-benzyloxypurine hydrate, which is a columnar crystal obtainedin Example 1.

FIG. 3 Shows ¹H-NMR of 2-amino-6-benzyloxypurine, which is a cubiccrystal obtained in Example 2.

FIG. 4 shows a microscopic photograph (magnification ×100, 1graduation=0.02 mm) of 2-amino-6-benzyloxypurine, which is a cubiccrystal obtained in Example 2.

FIG. 5 shows DSC of 2-amino-6-benzyloxypurine, which is a cubic crystalobtained in Example 2.

FIG. 6 shows powder X-ray diffraction of 2-amino-6-benzyloxypurine,which is a cubic crystal obtained in Example 2.

FIG. 7 shows ¹H-NMR of a 2-amino-6-benzyloxypurine methanolate, which isa columnar crystal obtained in Example 3.

FIG. 8 shows a microscopic photograph (1 cell=0.1 mm) of a2-amino-6-benzyloxypurine methanolate, which is a columnar crystalobtained in Example 3.

FIG. 9 shows DSC of a 2-amino-6-benzyloxypurine methanolate, which is acolumnar crystal obtained in Example 3.

FIG. 10 shows powder X-ray diffraction of a 2-amino-6-benzyloxypurinemethanolate, which is a columnar crystal obtained in Example 3.

FIG. 11 shows ¹H-NMR of 2-amino-6-benzyloxypurine without a solventmolecule, which is a columnar crystal obtained in Example 4.

FIG. 12 shows a microscopic photograph (1 cell=0.1 mm) of2-amino-6-benzyloxypurine without a solvent molecule, which is acolumnar crystal obtained in Example 4.

FIG. 13 shows DSC of 2-amino-6-benzyloxypurine without a solventmolecule, which is a columnar crystal obtained in Example 4.

FIG. 14 shows powder X-ray diffraction of 2-amino-6-benzyloxypurinewithout a solvent molecule, which is a columnar crystal obtained inExample 4.

FIG. 15 shows ¹H-NMR of a 2-amino-6-benzyloxypurine ethanolate, which isa columnar crystal obtained in Example 5.

FIG. 16 shows a microscopic photograph (1 cell=0.1 mm) of a2-amino-6-benzyloxypurine ethanolate, which is a columnar crystalobtained in Example 5.

FIG. 17 shows DSC of a 2-amino-6-benzyloxypurine ethanolate, which is acolumnar crystal obtained in Example 5.

FIG. 18 shows powder X-ray diffraction of a 2-amino-6-benzyloxypurineethanolate, which is a columnar crystal obtained in Example 5.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, a novel crystal and a novel solvateof 2-amino-6-benzyloxypurine, which have not been obtained before, canbe produced. The novel crystal that can be produced in the presentinvention includes a cubic crystal and a columnar crystal, and a solvatethat can be produced in the present invention is a hydrate or analcoholate (e.g., methanolate, ethanolate and the like). These crystalsprovided by the present invention are superior in filtration performanceand improved in operability as compared to conventional ones.

The production methods of a cubic crystal and a columnar crystal of2-amino-6-benzyloxypurine are explained in the following. It isessential to obtain a cubic crystal and a columnar crystal bycrystallization from a solvent containing at least one kind of solventselected from the group consisting of alcohol and water, and the shapeof the crystal can be determined by the temperature at the time of startof the precipitation of crystals (hereinafter to be referred to as aninitiation temperature (Ti)). To be specific, 2-amino-6-benzyloxypurineis dissolved in a solvent containing at least one kind of solventselected from the group consisting of alcohol and water, and crystalsare allowed to precipitate by appropriately setting the initiationtemperature (Ti). Ti varies depending on the solvent to be used, andwhen, for example, methanol (alone) is used as a solvent, Ti is adjustedto around 65° C. (60° C.-65° C.) to give a cubic crystal, and adjustedto 30° C.-55° C., preferably 40° C.-45° C., to give a columnar crystal.

For the production of a cubic crystal and a columnar crystal,2-amino-6-benzyloxypurine is dissolved in a solvent containing at leastone kind of solvent selected from the group consisting of alcohol andwater.

As the alcohol in the solvent containing at least one kind of solventselected from the group consisting of alcohol and water, which is usedfor the production of a cubic crystal and a columnar crystal, alcoholhaving 1 to 5 carbon atoms (e.g., methanol (MeOH), ethanol, propanol,isopropanol, butanol, pentyl alcohol and the like) can be used, withpreference given to methanol and ethanol.

The total amount of the solvent to be used for producing a cubic crystaland a columnar crystal is not subject to any particular limitation aslong as 2-amino-6-benzyloxypurine can be dissolved, and varies dependingon temperature of heating and the kind of solvent. When methanol (alone)is used as a solvent, for example, the amount is generally 10 ml-1000ml, preferably 10 ml-300 ml, relative to 1 g of2-amino-6-benzyloxypurine in the following temperature range.

The heating temperature for dissolving 2-amino-6-benzyloxypurine in asolvent containing at least one kind of solvent selected from the groupconsisting of alcohol and water is not particularly limited as long asit is not higher than the boiling point of the solvent and not lowerthan the temperature at which 2-amino-6-benzyloxypurine can bedissolved. When methanol (alone) is used as a solvent, it is generally30° C.-65° C., preferably 55° C.-65° C.

In the event an insoluble material is present in a solution obtained bydissolving 2-amino-6-benzyloxypurine in a solvent containing at leastone kind of solvent selected from the group consisting of alcohol andwater, the insoluble material is preferably removed for improvingpurity. For example, the obtained solution is hot filtrated to remove aninsoluble material. The hot filtration is conducted while maintainingthe dissolution state of 2-amino-6-benzyloxypurine, and the temperaturedepends on the solvent to be used. When methanol (alone) is used as asolvent, the filtration is conducted generally at 30° C.-65° C.,preferably at 50° C.-65° C.

The precipitation of a cubic crystal and a columnar crystal may bestarted by any means. For example, (1) 2-amino-6-benzyloxypurine isdissolved in a solvent containing at least one kind of solvent selectedfrom the group consisting of alcohol and water, and the obtainedsolution is cooled, (2) 2-amino-6-benzyloxypurine is dissolved in asolvent containing at least one kind of solvent selected from the groupconsisting of alcohol and water, and the solvent is partially removedfrom the obtained solution, and the like.

Before precipitation of crystals by the above-mentioned method (1) or(2), a poor solvent may be added to supersaturate the solution.

When the precipitation of crystal is started by the method of theabove-mentioned (1), the cooling temperature is set for Ti that affordsa desired crystal shape, and 2-amino-6-benzyloxypurine in the solventcontaining at least one kind of solvent selected from the groupconsisting of alcohol and water is cooled to reach supersaturation.

When the precipitation of crystal is started by the method of theabove-mentioned (2), The evaporation temperature is set for Ti thataffords a desired crystal shape, and the solvent is evaporated until2-amino-6-benzyloxypurine in the solvent containing at least one kind ofsolvent selected from the group consisting of alcohol and water reachessupersaturation.

Once a crystal having the desired shape starts to precipitate, coolingor evaporation thereafter does not necessarily require setting thetemperature for Ti. However, it is necessary to pay sufficient attentionto prevent dissolution of the precipitated crystals. The precipitatedcrystals may be taken out by any means, such as filtration.

A cubic crystal is obtained as one without a solvent molecule, and acolumnar crystal is obtained as a solvate (e.g., alcoholate, hydrate andthe like), both by the above-mentioned method. For example, a columnarcrystal can be converted to a crystal without a solvent molecule bydrying at a temperature for removing the solvent molecule. Theconversion to a crystal without a solvent molecule can be performed bydrying the collected crystals at generally 60° C.-200° C., preferably80° C.-120° C., in any solvent.

The production methods of an alcoholate and a hydrate of2-amino-6-benzyloxypurine are explained in the following. The alcoholateshould be obtained by crystallization from alcohol, and the hydrateshould be obtained by crystallization from a water-containing solvent.

As the alcohol to obtain the alcoholate, a solvent similar to alcoholused for the production of the above-mentioned novel crystal can beused. The amount of the alcohol to be used for producing the alcoholateis not subject to any particular limitation as long as2-amino-6-benzyloxypurine can be dissolved by heating, and variesdepending on heating temperature. When methanol (alone) or ethanol(alone) is used, for example, the amount is generally 19 ml-1000 ml,preferably 10 ml-300 ml, relative to 1 g of 2-amino-6-benzyloxypurinewhen the heating temperature is in the following range.

As the solvent other than water that is contained in thewater-containing solvent to be used for obtaining a hydrate, alcohol ispreferably used. As the alcohol to be used here, a solvent similar tothe above-mentioned alcohol used for the production of the novel crystalcan be used. As the water-containing solvent, water alone and a mixedsolvent of alcohol and water are preferably used. As the mixed solventof alcohol and water, a mixed solvent of methanol and water ispreferable in view of difference in solubility. The mixing ratio ofalcohol and water depends on the kind of alcohol. For example, in thecase of a mixed solvent of methanol and water, the volume ratio ofmethanol and water is 10:3-10:50, preferably 10:8-10:15.

The temperature for dissolving 2-amino-6-benzyloxypurine in each solventby heating is not particularly limited as long as2-amino-6-benzyloxypurine can be dissolved in each solvent at saidtemperature. When methanol is used, the temperature is generally 30°C.-65° C., preferably 55° C.-65° C. The crystallization method afterdissolution by heating is not particularly limited, and a method similarto crystallization in the production method of the above-mentioned novelcrystal can be employed.

When the precipitation of crystal is conducted by the method of theaforementioned (1) or (2), crystallization at Ti for a columnar crystalaffords a columnar crystal with a solvent molecule, and crystallizationat Ti for a cubic crystal affords a cubic crystal without a solventmolecule. Thus, a cubic crystal with a solvent molecule cannot beobtained. The precipitated crystals may be taken out by any means, suchas filtration.

When each crystal with a solvent molecule obtained is dried, it isnecessary to pay sufficient attention to drying conditions to preventremoval of the solvent molecule. The drying temperature is generally 10°C.-70° C., preferably 10° C.-50° C., for any solvate.

Each step for producing the novel crystal and solvate of the presentinvention may be carried out under atmospheric pressure, under reducedpressure, or under pressurization.

The 2-amino-6-benzyloxypurine to be used in the present invention may beproduced by any method. For example, it can be produced by the methoddescribed in JP-A-10-218880.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples. The present invention is not limit ed by theseexamples.

The conditions for the measurement of each property of the compoundsobtained in Examples and Reference Example are as follows.

DSC: measured using DSC-60 manufactured by Shimadzu Corporation.

¹H-NMR: A sample was dissolved in DMSO-d₆, which was measured byJNM-AL400 manufactured by JEOL Corporation.

microscopic photograph: photographed using SMZ1500 manufactured byNikon.

powder X-ray diffraction: measured using Mini Flex manufactured byRigaku Corporation.

Reference Example 1

Benzyl alcohol (37.5 g, 0.347 mol) and sodium hydroxide (2.96 g, 0.074mol) were mixed and heated, and sodium hydroxide was dissolved. Aftercooling, 2-amino-6-chloropurine (6.00 g, 0.035 mol) was added, and thereaction was completed by heating and stirring at 80-90° C. for 5 hr.Methyl tert-butyl ether (120 ml) was added to the reaction mixture, andthe mixture was extracted twice with 1% aqueous sodium hydroxidesolution (70 ml). The obtained aqueous alkali layers were combined,washed with toluene, and after removing toluene, neutralized with 35%hydrochloric acid to pH 6-8. The precipitated crystals were collected byfiltration. The obtained crystals were dried under reduced pressure togive 2-amino-6-benzyloxypurine (7.60 g, 0.032 mol, yield 92%) as crudecrystals.

Example 1

2-Amino-6-benzyloxypurine (40.0 g, 0.17 mol) obtained in ReferenceExample 1 was dissolved in methanol (700 ml) by heating under reflux(63° C.-65° C.). This solution was hot filtered (60° C.-63° C.), andthen methanol (350 ml) was evaporated under reduced pressure at 40°C.-45° C., as a result of which crystals started to precipitate. Water(400 ml) was added thereto, and the mixture was cooled to 0° C.-5° C. toallow further precipitation of crystals. After filtration, the crystalswere dried under reduced pressure at room temperature for 12 hr to givea 2-amino-6-benzyloxypurine hydrate (41.7 g, 0.16 mol, yield 97%) ascolumnar crystals. The reduction in amount by drying (110° C., 4 hr) was7.52%. The microscopic photograph of the obtained compound is shown inFIG. 1, and DSC thereof is shown in FIG. 2.

Example 2

2-Amino-6-benzyloxypurine (20.0 g, 0.083 mol) obtained in ReferenceExample 1 was dissolved in methanol (300 ml) by heating under reflux.This solution was hot filtered (60° C.-63° C.), and methanol (150 ml)was evaporated under atmospheric pressure at 63° C.-65° C., as a resultof which crystals started to precipitate. This was cooled to 0° C.-5° C.over 30 min. After filtration, the crystals were dried under reducedpressure at 50° C. for 6 hr to give a 2-amino-6-benzyloxypurine hydrate(17.9 g, 0.074 mol, yield 89%) as cubic crystals. The reduction inamount by drying (110° C., 4 hr) was 0.02%. The ¹H-NMR of the obtainedcompound is shown in FIG. 3, microscopic photograph thereof is shown inFIG. 4, DSC thereof is shown in FIG. 5 and powder X-ray diffractionthereof is shown in FIG. 6.

Example 3

2-Amino-6-benzyloxypurine (20 g, 0.083 mol) obtained in ReferenceExample 1 was dissolved in methanol (300 ml) by heating under reflux.This solution was hot filtered (60° C.-63° C.), and methanol (150 ml)was evaporated under reduced pressure at 40° C.-45° C., as a result ofwhich crystals started to precipitate. This was cooled to 0° C.-5° C.over 6 hr. After filtration, the crystals were dried under reducedpressure at 45° C. for 6 hr to give a 2-amino-6-benzyloxypurinemethanolate (21.5 g, 0.079 mol, yield 95%) as columnar crystals. Thereduction in amount by drying (110° C., 4 hr) was 13.4%. The ¹H-NMR ofthe obtained compound is shown in FIG. 7, microscopic photograph thereofis shown in FIG. 8, DSC thereof is shown in FIG. 9 and powder X-raydiffraction thereof is shown in FIG. 10.

Example 4

By drying the crystal (10 g, 0.036 mol) obtained in Example 3 underreduced pressure (15 mmHg) at 90° C. for 7 hr, 2-amino-6-benzyloxypurinewithout a solvent molecule (8.8 g, 0.036 mol) was obtained as columnarcrystals. The ¹H-NMR of the obtained compound is shown in FIG. 11,microscopic photograph thereof is shown in FIG. 12, DSC thereof is shownin FIG. 13 and powder X-ray diffraction thereof is shown in FIG. 14.

Example 5

By treating 2-amino-6-benzyloxypurine (20 g, 0.0083 mol) obtained inReference Example 1 in the same manner as in Example 3 except thatethanol (300 ml) was used instead of methanol, a2-amino-6-benzyloxypurine ethanolate (22.1 g, 0.078 mol, yield 9.3%) wasobtained as columnar crystals. The crystal started to precipitate whenthe solution was cooled. The temperature then was about 45° C. Thereduction in amount by drying (110° C., 4 hr) was 16.4%. The ¹H-NMR ofthe obtained compound is shown in FIG. 15, microscopic photographthereof is shown in FIG. 16, DSC thereof is shown in FIG. 17 and powderX-ray diffraction thereof is shown in FIG. 18.

INDUSTRIAL APPLICABILITY

According to the present invention, a novel crystal (cubic crystal orcolumnar crystal) and a solvate (hydrate and alcoholate (e.g.,methanolate, ethanolate) of 2-amino-6-benzyloxypurine, which have notbeen obtained before, and production methods thereof can be provided.

The crystal obtained by the method of the present invention is superiorin filtering performance and has improved operability as compared toconventional crystals.

This application is based on a patent application No. 2002-105805 filedin Japan, the contents of which are hereby incorporated by reference.

1. A 2-amino-6-benzyloxypurine solvate.
 2. A 2-amino-6-benzyloxypurinehydrate.
 3. A 2-amino-6-benzyloxypurine alcoholate.
 4. A2-amino-6-benzyloxypurine methanolate.
 5. A 2-amino-6-benzyloxypurineethanolate.
 6. A cubic crystal of 2-amino-6-benzyloxypurine.
 7. Acolumnar crystal of 2-amino-6-benzyloxypurine.
 8. A production method ofa cubic crystal or a columnar crystal of 2-amino-6-benzyloxypurine,which comprises crystallization from a solvent containing at least onekind of solvent selected from the group consisting of alcohol and water.9. A production method of a 2-amino-6-benzyloxypurine alcoholate, whichcomprises crystallization from alcohol.
 10. A production method of a2-amino-6-benzyloxypurine hydrate, which comprises crystallization froma water-containing solvent.
 11. The production method of claim 10,wherein the water-containing solvent is a mixed solvent of alcohol andwater.
 12. The production method of claim 10, wherein thewater-containing solvent is water.